RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer.

Abstract

INTRODUCTION:

PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown.

EXPERIMENTAL DESIGN:

We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models.

RESULTS:

We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1-wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment.

CONCLUSIONS:

Our data suggest that in both BRCA1-mutant and BRCA1-wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514-22. ©2016 AACR.

• Authors: Yajing Liu, Monika L Burness, Rachel Martin-Trevino, Joey Guy, Shoumin Bai, Ramdane Harouaka, Michael D Brooks, Li Shang, Alex Fox, Tahra K Luther, April Davis, Trenton L Baker, Justin Colacino, Shawn G Clouthier, Zhi-Ming Shao, Max S Wicha, Suling Liu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 2 Pg. 514-522 (Jan 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28034904 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• Poly(ADP-ribose) Polymerase Inhibitors
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Rad51 Recombinase

Topics

• Animals
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Neoplasm Metastasis
• Neoplasm Recurrence, Local (genetics, pathology)
• Neoplastic Stem Cells (drug effects)
• Poly (ADP-Ribose) Polymerase-1 (genetics)
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage)
• Rad51 Recombinase (genetics)
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)
• Xenograft Model Antitumor Assays